1. Field of the Invention
The present invention relates generally to the field of pain management, and in particular, the management of neuropathic or inflammatory pain including a neuropathic or inflammatory component of nociceptive pain. More particularly, the present invention provides methods and compositions which treat, alleviate, prevent, diminish or otherwise ameliorate the symptoms of neuropathic or inflammatory pain. The present invention further contemplates combination therapy involved in the treatment of pain in association with the treatment of a particular disease condition or pathology. The present invention further also provides sustained and slow release formulations, tamper-proof deliver systems and stents, catheters and other mechanical devices coated with formulations which permit sustained or slow release of active ingredients involved in pain management.
2. Description of the Prior Art
Bibliographical details of references provided in the subject specification are listed at the end of the specification.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in such terms. In considering approaches to treatment of pain, it is important to understand the distinction between acute and persistent or chronic pain. Acute pain occurs as a result of tissue injury, and is mediated by chemical, mechanical or thermal stimulation of pain receptors known as nociceptors. In contrast to acute pain, chronic or persistent pain in itself constitutes a disease which serves no protective biological function. Chronic pain is unrelenting and can persist for years and frequently cannot be associated with a single injury. Chronic pain predominantly constitutes chronic inflammatory pain (e.g. arthritis) or “neuropathic pain” which can be defined as pain initiated or caused by a primary lesion or dysfunction within the nervous system (Mersky and Bogduk Classifications of Chronic Pain, 2nd edn. Seattle IASP Press: 394, 1994, De Andres and Garcia-Ribas Pain Practice 3:1-7, 2003). Neuropathic pain is associated with a variety of disease states and present in the clinic with a wide range of symptoms. (Woolf and Mannion Lancet 353:1959-64, 1999) It does not require specific pain receptor stimulation although such stimulation can add to the intensity of the pain sensation (Baron Clin J Pan 16 (suppl2):S12-S20, 2003).
Neuropathic pain is often reported as having a lancinating or continuous burning character and is frequently associated with the appearance of abnormal sensory signs such as allodynia and hyperalgesia. Alloydnia is defined as pain resulting from a stimulus that does not normally elicit a painful response, and hyperalgesia is characterized by an increased pain response to normally non-painful stimuli. Some disorders characterized by neuropathic pain include monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndromes, back pain and the various peripheral neuropathies. Neuropathic pain may also be associated with diabetes, radio- or chemo-therapy and infections such as HIV. Neuropathic pain may also result as a side effect of drug treatment or abuse.
For clinical purposes, nociceptive pain can be classified as somatic or visceral. Somatic pain results from prolonged activation of nociceptive receptors in somatic tissues such as a bone, joint, muscle or skin. Visceral pain, on the other hand manifests from activation of nociceptive receptors by pathological mechanisms such as mechanical injury, x-ray irradiation and toxic agents.
Neuropathic pain can be characterized by the following clinical features (Teng and Mekhail Pain Practice 3:8-12, 2003, Rajbhandari et al Pain, 83:627-629, 1999, Melzack et al Ann NY Acad Sci, 933: 157-174, 2001):
1. There is the presence of an abnormal, unpleasant sensation (dysesthesia) that frequently has a burning or electrical quality with an occasional paroxysmal, brief, shooting, or stabbing quality.
2. Although the onset of most neuropathic pain is within days after the precipitating injury, there is no absolute temporal relationship to the originating neural trauma such that it can begin weeks, months, or even years later.
3. Pain may be felt in a region of sensory deficit.
4. Non-noxious stimuli may be painful (allodynia).
5. Noxious stimuli may produce greater than normal response (hyperalgesia).
6. There may be an increase in the intensity of pain with repeated stimuli and the pain may persist after the removal of stimuli.
There are no analgesic agents specific for one type of pain component over another and neuropathic and nociceptive pains often respond differently to various analgesics.
Accordingly, although there are numerous available therapies for acute pain caused by stimulation of the nociceptors, especially treatment with opioid and non-steroidal anti-inflammatory drugs (NSAIDs), neuropathic pain is an area of largely unmet therapeutic need. Due to the distinct pathophysiochemical mechanisms and clinical manifestations associated with neuropathic pain relative to pain caused as a result of nociceptor stimulation or acute pain, agents useful in the treatment of pain caused as a result of nociceptor stimulation or acute pain have reduced effectiveness in neuropathic pain treatment. In particular, the effectiveness of opioids in the treatment of neuropathic pain is diminished relative to their use in the treatment of pain caused as a result of nociceptor stimulation or acute pain, and drug dose response curves for treatment of neuropathic pain are shifted to the right of those for treatment of pain caused as a result of nociceptor stimulation or acute pain (Teng and Mekhail, 2003 supra, De Andres and Garcia-Ribas, 2003 supra, Stute et al J. Pain Symptom Management 25:1123-1131, 2003).
Due to the diminished effects of opioids in subjects suffering from neuropathic pain, the use of opioids is often frequent and sustained. This over use is often associated with addiction, the development of tolerance and an increase in the number and severity of side effects associated with opioid use. These side effects include euphoric effects, emetic effects, spastic constipation and increased smooth muscle tone.
The conventional pharmacological mainstays of clinical management of neuropathic pain are the tricyclic anti-depressants and certain anti-convulsants, but even these achieve a reduction in pain of less than 50% in greater than 50% of patients treated. These agents are also associated with significant side effect profiles.
There is a pressing need for improved regimes for the treatment of neuropathic and inflammatory pain as well as improved regimes for treating disease conditions which have a neuropathic or inflammatory pain component.